Carboxylic acid esters of N-hydroxysuccinimide (NHS) have been widely used in organic synthesis as reactive acylating reagents (a.k.a. active esters). These active esters are especially useful as intermediates in the synthesis of peptides and proteins via N-acylation. The chemistry of N-hydroxysuccinimido esters has been reviewed Cline et al [J. Am. Chem. Soc. 1987, 109, 3087–3091] and by Hirata et al. [Yukagaku 1991, 40, 1088–1094]. These and all other patents and literature references cited in this application are incorporated herein by reference. The classical methods for making N-hydroxysuccinimido esters include (a) the reaction of the sodium, potassium, silver or thallium salt of N-hydroxysuccinimide with an acyl chloride; (b) esterification of a carboxylic acid with NHS in the presence of a carbodiimide; (c) esterification of a carboxylic acid with NHS in the presence of azodicarboxylate/triphenylphosphine; (d) reaction of bis(N-succinimidyl) carbonate with carboxylic acid; and (e) acylation of NHS with mixed anhydrides. The processes of the art commonly begin with a carboxylic acid, convert it to an N-hydroxysuccinimido ester, and react the N-hydroxysuccinimido ester with an amine to provide an amide.
The recent publication [PCT application WO 02/36573] of amide bioisosteres of 8-hydroxy-2,6-methano-3-benzazocines and 3-hydroxymorphinanes has stimulated interest in methods for direct conversion of phenols to amides. Such a process would be useful for producing compounds having activity as analgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants, antitussives, anorexics and as treatments for hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain (including neuropathic pain), irritable bowel syndrome and gastrointestinal motility disorders.